Mechanisms of Action of Hydroxychloroquine in Reducing Risk of Type 2 Diabetes. Diabetes is approaching epidemic proportions in the United States. Efforts to implement effective strategies for diabetes prevention have been limited by poor long-term adherence to lifestyle modifications and potential side effects and costs of pharmacologic interventions. We recently showed that long-term use of hydroxychloroquine (HCQ), an antimalarial used to treat rheumatoid arthritis is associated with an impressive 77% reduction in risk of diabetes when taken for more than 4 years. This protective association increases with greater duration of use. In patients with well established Type 2 diabetes mellitus (T2DM), HCQ has a positive effect on glycemic control. In spite of its efficacy and excellent safety profile, HCQ is not used to treat T2DM because of potential retinal toxicity, a very rare though feared side effect unrelated to vascular disease or T2DM. The precise mechanism(s) by which HCQ attenuates diabetes risk have not been determined. Here we propose a pilot and feasibility clinical trial of HCQ in subjects with pre-diabetes. In this pilot and feasibility clinical trial, we will study changes in beta-cell function (insulin secretion) and insulin sensitivity associated with short-term HCQ therapy compared with placebo using frequent sampling intravenous glucose tolerance testing (FSIGTT) methodology. We propose to 1) determine the short-term effects of HCQ (600 mg/d orally) on beta-cell function, insulin disposition index, and insulin sensitivity in subjects with pre-diabetes and 2) determine the change in insulin secretion, disposition index and sensitivity 3 months after HCQ cessation. Thirty overweight or obese pre- diabetic subjects with a family history of T2DM will be randomized to receive HCQ or placebo for 3 months. We will determine insulin secretion and insulin resistance using FSIGTT at baseline and 3 months in all subjects, and again after 3 month drug washout in the HCQ-treated subjects only. We hypothesize that insulin secretion and sensitivity will improve in subjects with pre-diabetes treated with HCQ for 3 months. Based on its long half-life and increasing effect on diabetes risk with prolonged exposure, we expect that the effects of HCQ on pre-diabetic subjects will persist, albeit marginally smaller, 3 months after drug cessation. Given HCQ's potential clinical utility as an alternative to current drugs used to delay or prevent the onset of T2DM, this pilot and feasibility study will provide preliminary data to assist in planning a T2DM prevention trial of HCQ in high-risk subjects. The rapidly increasing occurrence of Type 2 diabetes has become a pressing public health concern. Approaches to prevent this debilitating disease include diet and lifestyle modification as well as drug therapy. The current study attempts to document the ability of a relatively safe and inexpensive drug treatment to prevent diabetes in overweight people at high risk for developing the disease. PUBLIC HEALTH RELEVANCE: This pilot clinical trial of hydroxychloroquine compared with placebo in humans will examine the mechanism(s) of action of the drug in attenuating the risk of type 2 diabetes mellitus (T2DM) in patients with pre-diabetes. Results will be used to design a large-scale clinical trial to determine the effect of this drug in preventing or delaying the development of T2DM in subjects at high risk.